tbuckley/cabot-search huggingface dataset:
Therapeutic Potential of Targeting Prokineticin Receptors in Diseases
Authors: Martina Vincenzi, Amin Kremić, Appoline Jouve, Roberta Lattanzi, Rossella Miele, Mohamed Benharouga, Nadia Alfaidy, Stephanie Migrenne-Li, Anumantha G. Kanthasamy, Marimelia Porcionatto, Napoleone Ferrara, Igor V. Tetko, Laurent Désaubry, Canan G. Nebigil
Journal: Pharmacological Reviews (2023)

The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. <h3>Significance Statement</h3> This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits "constitutive" activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.
Follicular lymphoma evolves with a surmountable dependency on acquired glycosylation motifs in the B-cell receptor
Authors: Sarah Haebe, Grady Day, Debra K. Czerwinski, Anuja Sathe, Susan M. Grimes, Tianqi Chen, Steven R. Long, Brock Martin, Michael G. Ozawa, Hanlee P. Ji, Tanaya Shree, Ronald Levy
Journal: Blood (2023)
Artificial intelligence for breast cancer detection in screening mammography in Sweden: a prospective, population-based, paired-reader, non-inferiority study
Authors: Karin Dembrower, Alessio Crippa, Eugenia Colón, Martin Eklund, Fredrik Strand
Journal: The Lancet Digital Health (2023)

BackgroundArtificial intelligence (AI) as an independent reader of screening mammograms has shown promise, but there are few prospective studies. Our aim was to conduct a prospective clinical trial to examine how AI affects cancer detection and false positive findings in a real-world setting.MethodsScreenTrustCAD was a prospective, population-based, paired-reader, non-inferiority study done at the Capio Sankt Göran Hospital in Stockholm, Sweden. Consecutive women without breast implants aged 40–74 years participating in population-based screening in the geographical uptake area of the study hospital were included. The primary outcome was screen-detected breast cancer within 3 months of mammography, and the primary analysis was to assess non-inferiority (non-inferiority margin of 0·15 relative reduction in breast cancer diagnoses) of double reading by one radiologist plus AI compared with standard-of-care double reading by two radiologists. We also assessed single reading by AI alone and triple reading by two radiologists plus AI compared with standard-of-care double reading by two radiologists. This study is registered with ClinicalTrials.gov, NCT04778670.FindingsFrom April 1, 2021, to June 9, 2022, 58 344 women aged 40–74 years underwent regular mammography screening, of whom 55 581 were included in the study. 269 (0·5%) women were diagnosed with screen-detected breast cancer based on an initial positive read: double reading by one radiologist plus AI was non-inferior for cancer detection compared with double reading by two radiologists (261 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·04 [95% CI 1·00–1·09]). Single reading by AI (246 [0·4%] vs 250 [0·4%] detected cases; relative proportion 0·98 [0·93–1·04]) and triple reading by two radiologists plus AI (269 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·08 [1·04–1·11]) were also non-inferior to double reading by two radiologists.InterpretationReplacing one radiologist with AI for independent reading of screening mammograms resulted in a 4% higher non-inferior cancer detection rate compared with radiologist double reading. Our study suggests that AI in the study setting has potential for controlled implementation, which would include risk management and real-world follow-up of performance.FundingSwedish Research Council, Swedish Cancer Society, Region Stockholm, and Lunit.
A just transition for antimicrobial resistance: planning for an equitable and sustainable future with antimicrobial resistance
Authors: Sheila Rose Varadan, Clare Isobel Rosina Chandler, Kym Weed, Syed Masud Ahmed, Caesar Atuire, Deepshikha Batheja, Susan Jane Bull, Sander Chan, Hindrik Rogier van Doorn, Ashish Giri, René Gerrets, Steve Hinchliffe, Calvin Ho, Pablo Imbach, Marina Joubert, Claas Kirchhelle, Taciano L Milfont, Sassy Molyneux, Edna Nduku Mutua, Christopher Pell, Nenene Qekwana, Yin Mo, Phaik Yeong Cheah, Sonia Lewycka
Journal: The Lancet (2023)
Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti–PD-1 in head and neck cancer
Authors: Giacomo Oliveira, Ann Marie Egloff, Alexander B. Afeyan, Jacquelyn O. Wolff, Zexiang Zeng, Rebecca D. Chernock, Liye Zhou, Cameron Messier, Patrick Lizotte, Kathleen L. Pfaff, Kari Stromhaug, Livius Penter, Robert I. Haddad, Glenn J. Hanna, Jonathan D. Schoenfeld, Laura A. Goguen, Donald J. Annino, Vickie Jo, Peter Oppelt, Patrik Pipkorn, Ryan Jackson, Sidharth V. Puram, Randal C. Paniello, Jason T. Rich, Jason Webb, Jose P. Zevallos, Mena Mansour, Jingxin Fu, Gavin P. Dunn, Scott J. Rodig, Jessica Ley, Luc G. T. Morris, Lara Dunn, Cloud P. Paweletz, Dorina Kallogjeri, Jay F. Piccirillo, Douglas R. Adkins, Catherine J. Wu, Ravindra Uppaluri
Journal: Science Immunology (2023)

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8
Innate receptors with high specificity for HLA class I–peptide complexes
Authors: Malcolm J. W. Sim, Paul Brennan, Katherine L. Wahl, Jinghua Lu, Sumati Rajagopalan, Peter D. Sun, Eric O. Long
Journal: Science Immunology (2023)

Genetic studies associate killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands with a variety of human diseases. The basis for these associations and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. Because KIR binding to HLA-I is peptide dependent, we performed systematic screens, which totaled more than 3500 specific interactions, to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic and could bind ~60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10% and down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C, with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germline-encoded NK receptors and suggest that NK cell responses can be shaped by HLA-I-bound immunopeptidomes in the context of disease or infection.
The UK is rejoining Horizon Europe: separating the spin from the substance
Authors: Martin McKee
Journal: BMJ (2023)

The announcement, on 7 September 2023, that the EU and UK had agreed, in principle, that the latter would associate with the 2022-2027 Horizon Europe research programme was greeted with virtually universal relief by scientific communities in both jurisdictions.While the estimated €2.6 billion of funding linked to British participation is very welcome, the greater benefit will be the new opportunities for British based scientists to join with colleagues in other countries, not just in the EU, to seek solutions to some of humanity's most pressing challenges.Competing interests: MM is an investigator on two Horizon Europe projects and on the advisory board of another.Until recently he managed an ERASMUS+scheme.
P02.26.B METABOLIC PLASTICITY IN GLIOBLASTOMA TUMOR-INITIATING CELL AND RESISTANCE TO LSD1-DIRECTED THERAPY
Authors: G Marotta, B Costanza, D Osti, S Faletti, E Zaccheroni, C Richichi, M Del Bene, G Pelicci
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM), the most common primary brain tumor in adults, remains incurable despite multimodal therapy. There is a pressing unmet medical need for new therapeutic strategies, especially because patients experience only short-term benefit after primary treatment and the vast majority inevitably relapse. Adaptation to harsh microenvironmental conditions, including nutrient deprivation, proteostasis perturbation, hypoxia and drug treatment, induce molecular and metabolic changes in glioblastoma that lead to the acquisition of a tolerance to stress and resistance to drug. In this context, we demonstrated that Lysine-specific histone demethylase 1 (LSD1) is a regulator of tumor-initiating cell (TICs) survival, adaptation and recovery from stress. LSD1 pharmacological inhibition with a specific and brain penetrant inhibitor (LSD1i) induces a maladaptive integrated stress response (ISR) which leads to the death of TICs exposed to ER stress or nutrient deficiency. MATERIAL AND METHODS Given the high GBM heterogeneity, we analyzed different patient-derived TICs grown in vitro as sphere and characterized for their genetic landscape and in vitro/in vivo stem cell-like features. We applied mechanistically different strategies, including biological, metabolic and pharmacological approaches, as well as transcriptomic and proteomic profiling. Zebrafish and GBM xenografts have been exploited as in vivo models. RESULTS LSD1i treatment induces physical and functional rearrangements of mitochondria, culminating into their enhanced bioenergetic activity and ATP production that predispose to cell death. Interestingly, only a subset of patient-derived TICs benefits from LSD1i therapy. These samples are largely dependent on glycolysis and, upon LSD1i administration, they are unable to further enhance it when mitochondrial energy production is inhibited. The samples resistant to LSD1i maintain their cellular behavior unaltered even upon prolonged treatment. They display reduced susceptibility to the stressful cues represented by either LSD1i and the known ER stressors Thapsigargin and Tunicamycin, by efficiently restoring energy homeostasis and properly activating the Activating Transcription Factor 4 (ATF4)-dependent ISR. Remarkably, LSD1i resistant samples display metabolic flexibility and switch between glycolytic and oxidative metabolism to ensure their survival. CONCLUSION The identification of specific metabolic vulnerabilities could offer unique opportunities for therapeutic intervention: the selective LSD1i vulnerability relies on the preferential dependence on glycolysis, while the great metabolic plasticity of LSD1i resistant TICs coordinates changes that favor their adaptation to stressful microenvironments and therapeutic insults.
P02.03.A INTEGRATIVE (EPI)GENETIC ANALYSIS OF INVASION-PROMOTING GENES IN HIGH-GRADE GLIOMA CELLS
Authors: T Müller, M Mittelbronn, A Hau
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DNA methylation-based analyses of brain tumors including glioma is currently the gold standard for diagnostic classification. Aberrant epigenetic alterations can lead to inappropriate gene expression and thereby promote tumorigenesis. Glioblastoma (GBM), CNS WHO grade 4, is characterized by a very diffuse infiltrative growth into the adjacent brain parenchyma. Due to these highly invasive but also genetically heterogeneous and plastic cellular phenotypes, standard treatment, including maximum resection, radio- and chemotherapy, has limited efficacy. It can be assumed that intertumoral or molecular heterogeneity of gliomas on transcriptional level is caused by altered epigenetic changes within the individual tumor cells. Considering this, we hypothesize that tumor cell invasion being one of the critical hallmarks of highly malignant gliomas goes along with altered DNA methylation status and following from this changes in invasion-promoting transcript expression. MATERIAL AND METHODS We performed several in vitro screening approaches to describe the genetic, epigenetic and transcriptional status of invasion glioma cells. Within our first approach, we isolated fractions of glioma cells with increased invasive properties and performed Illumina® array-based methylation profiling as well as RNA sequencing analysis to identify methylation-driven, invasion-associated gene sets. During a second approach, the inducible CRISPR/Cas9 Synergistic Activation Mediator (SAM) system and a genome-wide sgRNA library were introduced in a serum-free glioma cell line. During CRISPR/Cas9 SAM mediated single-gene activation cells were subjected to a transwell invasion assay and sgRNA representation within the invasive glioma cell fraction was determined by next-generation-sequencing (NGS). RESULTS In this study, we integrated Illumina HumanMethylation850K methylation data, RNA-sequencing data and invasion-promoting sgRNA representation data. By systemic screening we identified an invasion-promoting gene signature and the correlating promotor DNA-methylation status. Future studies will be directed to further investigate the impact of identified genes in invasion of high-grade glioma cells. CONCLUSION This integrative experimental approach complements existing genome-wide inhibitory screens as well as incorporates for the first time DNA-methylation profiles and transcriptome analysis with gene-sets identified by CRISPR/Cas9 activation screen and thereby holds the potential to identify novel invasion-essential candidate genes.
OS08.7.A DEPRESSIVE SYMPTOMS IN ASSOCIATION WITH TUMOR LOCATIONS AT DIAGNOSIS IN PATIENTS WITH DIFFUSE GLIOMA
Authors: M N G van Genderen*, V Belgers*, L Douw, F Barkhof, M Klein, J M Niers, R S Eijgelaar, P C de Witt Hamer
Journal: Neuro-Oncology (2023)

Abstract BACKROUND Depressive symptoms are common in glioma patients and occur more frequent than in patients with other cancer types. The presence of tumors in specific brain regions that potentially disturb brain functions could contribute to this difference. These lesions may cause an inadequate emotional response to an incurable and lethal disease with consequences for patient counseling and neurosurgical strategies. In this study, we examine the association between brain tumor location and depressive symptoms at presentation in patients with diffuse glioma using several methods for lesion symptom mapping. MATERIAL AND METHODS The retrospective cohort consisted of patients with diffuse glioma who had a preoperative MR-scan and completed the Center for Epidemiologic Studies Depression scale (CES-D) before treatment. We classified patients based on unexpectedly low ( ≤6), intermediate (7-20) and unexpectedly high (&amp;gt;20) CES-D scores. Tumors were segmented in 3D and corresponding white matter disconnectomes were derived from normative tractography. We first correlated tumor and disconnectome with CES-D using sparse canonical correlation analysis to identify clusters of associated brain voxels. Next, we assessed the association between tumor locations and CES-D category using Bayesian multivariable categorical regression analysis of patient and tumor characteristics, including the overlap of tumors and disconnectomes with specific brain atlas structures, the probability of disconnection of white matter tracts, and functional network changes in local efficiency and eigenvector centrality. RESULTS We included 201 patients with a median age of 45 years (range 18-81), consisting of 62% males and 29% grade 4 gliomas. CES-D was completed a median of three weeks before surgery, was unexpectedly low in 29% and unexpectedly high in 15% of patients. Tumors located in the left (L) pallidum and right (R) thalamus were related to unexpectedly low CES-D, whereas tumors in the L hippocampus, L nucleus accumbens and R putamen were related to unexpectedly high CES-D. Disconnection of the R temporal subsection of the cingulum bundle, L optic radiation, L superior longitudinal fasciculus I and L uncinate fasciculus (UF) were related to unexpectedly low CES-D, whereas disconnection of the R corticospinal tract, R fornix, and L UF were related to unexpectedly high CES-D. Neither voxel clusters nor network measures were associated with CES-D. CONCLUSION Both unexpectedly low and unexpectedly high depressive symptom burden is common in patients with diffuse glioma at presentation. These dysfunctional emotional responses may be associated with the location of the tumor. Awareness of this phenomenon may be important in patient counseling and neurosurgical strategies. * these authors contributed equally
OS13.5.A MOLECULAR CHARACTERISTICS AND PROGNOSTIC BIOMARKERS OF CENTRAL NEUROCYTOMA
Authors: M Krech, A Muench, D Teichmann, P Kuzman, M Münther, K Weber, K Wenger-Alakmeh, J Onken, P Vajkoczy, F Behling, S May, G Ntoulias, J K Krauss, O Atallah, M Esmaeilzadeh, W C Mueller, F L Heppner, A Koch, D Capper, D Kaul, W Paulus, K H Plate, R Beschorner, J E Neumann, C Hartmann, C Thomas, L Schweizer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Central neurocytomas (CN) are intraventricular brain tumors predominantly arising in young adults. Long-term prognosis is favorable in the majority of cases, whereas a considerable proportion of patients experience disease progression. Progression risk is currently assessed morphologically based on the presence of histological signs of atypia and/or an elevated ki67 proliferation index (&amp;gt;3%). The molecular profile and etiology of CN remains elusive and molecular biomarkers for risk stratification have not been identified yet. MATERIAL AND METHODS We analyzed a retrospective multi-institutional cohort of 108 CNs by genome-wide DNA methylation profiling. DNA whole exome sequencing was performed in 12 cases. Follow-up information was available for 45 patients. RESULTS The histological diagnosis of neurocytoma was epigenetically confirmed in 96 cases. 12/108 cases (11%) were assigned to another methylation class based on the v12.5 Heidelberg Brain Tumor Classifier. Median age at diagnosis was 29 years, distribution among sexes was equal. Based on morphology and immunohistochemistry, tumors were diagnosed as classical CN (n = 71), CN with increased proliferation (n = 10) and atypical CN (n = 15). In 49/72 cases (68%, NA=24), an elevated Ki67 above 3% was reported. DNA whole exome sequencing revealed no recurrent genetic alterations. Most copy number profiles were balanced (n = 87), while some cases (n = 9) showed individual chromosomal alterations (e.g. chr. +5, n = 3). Tumor recurrence was observed in 16/45 (36%, NA = 51) of cases. Median progression-free survival (PFS) after the initial diagnosis was 72 months, none of the patients died (observation time: range 3 - 141 months). In 16 cases, surgery was followed by adjuvant radiotherapy, predominantly in patients with subtotal resection (STR: n = 11, 69%; GTR: n = 5). There was no significantly different outcome between classical and atypical CNs (n = 45; median PFS 73 months vs. 26 months, p-value = 0.067) and cases with low vs. elevated Ki67 (n = 45; median PFS NA vs. 72 months, p-value = 0.44). CONCLUSION Preliminary data of our study indicate that histological diagnosis and Ki67 proliferation rate were not associated with PFS in epigenetically defined neurocytomas. Further research using clinical and molecular covariates is necessary to identify novel biomarkers to predict recurrence risk and benefit from adjuvant radiotherapy.
P07.04.A ELASTIC IMAGE FUSION OF INTRAOPERATIVE ULTRASOUND AND PREOPERATIVE MRI FOR IMPROVING NAVIGATION ACCURACY IN BRAIN TUMOR SURGERY
Authors: J S Onken
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In brain surgery, neuronavigation based on preoperative MRI is limited by various physical and operational factors, such as surgery-induced brain shift. Using navigated intraoperative ultrasound (iUS) imaging and 3D iUS image reconstruction may help improve neuronavigation. However, the registration of MRI and US scans can lead to spatial inconsistencies between the two modalities. This study aims to evaluate the clinical integration of navigated iUS imagining and its potential to improve the accuracy of resection during brain tumor surgery by comparing the performance of rigid and elastic MRI-iUS image fusion algorithms during retrospective evaluation. MATERIAL AND METHODS N = 50 patients with brain tumors were prospectively enrolled in this trial. The neuronavigation system (BrainLab AG) used in the study allowed for the reconstruction and integration of 3D iUS imaging, which was acquired multiple times throughout the surgery using a tracked ultrasound probe (BK Medical). Prototypes of automatic rigid and elastic MRI-iUS image fusion algorithms (Brainlab Elements Image Fusion) were retrospectively applied to improve co-registration accuracy between the MRI and iUS data. To evaluate the image co-registration accuracy, anatomical landmarks were defined in the MRI and iUS scans and used to measure Euclidean distances between each landmark pair. RESULTS Improvements in the image quality over the course of the study indicated that skills in US handling are essential. Contrast behavior and tumor structure influence the visibility of the tumor in the US. Artifacts caused by hemostatic agents challenge the US image quality and the fluid-filled resection cavity requires experience in probe handling. In terms of image fusion, significant mismatches of the iUS and MRI data were reported. For scans acquired before resection, rigid fusion using a novel co-registration algorithm may enhance the registration accuracy with mean target registration errors for two representative patients of 6.5/8.9 mm and 3.7/3.4 mm before and after registration update, respectively. For iUS scans acquired after tumor resection, rigid fusion is inherently limited due to non-linear brain shifts. Therefore, elastic image fusion has been applied to provide deformable MR-iUS image co-registration. CONCLUSION Navigated iUS imaging can be integrated into clinical routine and the use of MR-iUS image co-registration for updating navigation is a promising tool to compensate brainshift during surgical resection. However, further studies are needed to quantify the accuracy and assess whether iUS could potentially replace the use of iMRI in resection control of selected cases.